Pediatric CFS in a Community-Based Sample
Principal Investigator: Leonard A. Jason, Ph.D.
Project Director: Pamela Fox, Ph.D.
Co-Investigator: Ben Katz, M.D.
A grant funded by the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH
Existing published pediatric epidemiologic CFS studies are similar to the first generation of adult CFS prevalence studies in that they have had either poor sampling plans (e.g., recruitment at medical centers; Nijhof et al., 2011), or systematic biases that excluded certain people such as youth of lower socioeconomic status and those of color who were less likely to have access to health care (Dobbins et al., 1997), or failed to include a medical examination (Jones et al., 2004). We will determine the prevalence of pediatric CFS in a demographically diverse sample of participants unbiased by illness, help-seeking behaviors, or differential access to the health care system. This study will determine the prevalence of pediatric CFS in a community-based sample, as well as the relative frequency of CFS among various groups (e.g., different age groups, genders).
A Prospective Study of CFS Following Infectious Mononucleosis in College Students
Principal Investigators: Leonard A. Jason, Ph.D. and Ben Katz, MD
Project Director: Kristen Gleason, Ph.D.
A grant funded by the National Institute of Allergy and Infectious Diseases, NIH
About 12% of young adults will meet the criteria for chronic fatigue syndrome (CFS) 6 months following infectious mononucleosis (IM) (Katz et al., 2011). IM appears to be a predisposing factor for some individuals who develop CFS. Many candidate psychological and biological risk factors have been proposed to explain this phenomenon, but almost all lack prospective data from before the patients became ill with either IM or CFS. Some students develop IM while in college. Many student health services have students who use their services when they are medically well (e.g., for sports-related injuries and birth control). Our study will enroll Northwestern University (NU) students who use the university based health services when medically well, as well as after they develop IM and CFS. We will gather biological and psychological data when students are well, when they develop IM, and when they develop CFS. At the end of the 3 year recruitment period, we will continue to follow those who have developed CFS for 12 months. We will collect data regarding candidate biological and psychological factors thought to be related to the development of CFS, such as previous stressful life events, “action proneness”, coping skills, autonomic dysfunction, cytokine levels and the severity of the IM itself. Our proposed study will compare these prospective pre-illness (IM) variables to post-illness (IM) data between students who do and do not go on to develop CFS. This study will be able to identify risk factors for the development of CFS following IM. We have the unique ability to implement this prospective study with a “captive” and high-risk population for the development of IM and CFS.
A Comprehensive Service Delivery Model for Helping People with Chronic Fatigue Syndrome
(This grant was never funded but it serves as an example of what could occur for patients with this illness)
Chronic fatigue syndrome (CFS) is a debilitating illness that affects hundreds of thousands of people in the US. It is one of the most debilitating medical conditions that affects all aspects of life, including employment and activities of daily living. To date, no effective comprehensive treatment and assessment program exists to address both the medical and social service needs of individuals within the CFS population. This proposal describes a multidisciplinary, Chronic Fatigue Syndrome Assessment and Treatment Center where individuals with CFS can be individually assessed and where treatment can be specifically tailored to meet the unique needs of the patients. Ultimately, this project will enhance the welfare of individuals with CFS both directly, through the delivery of services, and indirectly, through public education and the increased allocation of resources. There is a need to develop model programs that can ultimately be disseminated to those individuals with CFS who need these services.
The Center will provide a thorough and individualized assessment, which will lead to access to medical and social services provided by practitioners that are specialized in the area of CFS. A comprehensive treatment plan will be developed for each client based on that individual’s need, and this might include focusing on increasing the physical, social, psychological, and occupational functioning of individuals with CFS. The Center will also provide resources to educate individuals with CFS and their families about the illness. Based on individual needs, the Center will link individuals with CFS with needed assistance such as financial assistance, housing, and activities of daily living. Emphasis will be placed on providing individuals with CFS with a support network of other individuals with CFS and service providers. Patients will be empowered by actively participating in the identification of what is offered in the comprehensive center. Services available through the Center will be developed through the collaboration of on site and local health and social service professionals, and in conjunction with experts in the area of CFS, and guidance through the local CFS self-help organization.
The Center will also address the needs of individuals with CFS through advocacy services. This involves educating the public, particularly medical and vocational service providers, about the nature and treatment of CFS, and about the services offered by the Center. The Center will work towards change at a larger level, increasing by its request on behalf of patients, the provision of effective services and resources for this population. We intend that these efforts will increase the acceptance and acknowledgement of CFS, and that the public, both general and medical, will become more responsive to the needs of individuals with this disabling disease.
Chronic fatigue syndrome appears to be a heterogeneous disease syndrome that may be triggered by a variety of factors (Jason et al, 1995). The most prominent symptom is persistent fatigue for at least 6 months. Other symptoms commonly reported include: mild fever or chills, sore throats, painful lymph nodes, unexplained generalized muscle weakness, muscle discomfort, prolonged generalized fatigue after levels of exercise, generalized headaches, joint swelling, neuropsychiatric complaints, and sleep disturbances. Relatively few patients are cured, with most continuing to experience decreases in exercise tolerance and mild symptoms related to their chronic fatigue syndrome, and these symptoms are exacerbated during periods of stress and minor illness. Wilson et al. (1994) recontacted 103 chronic fatigue syndrome patients after a three and a half year follow-up, and most remained functionally impaired (only 6 had completely recovered). Chronic fatigue syndrome is one of the most debilitating medical conditions when quality of life indicators are measured (Anderson & Ferrans, 1997).
Many physicians continue to believe that most patients with this disease are suffering from a psychiatric illness. These biases have been filtered to the media, which has portrayed chronic fatigue syndrome in simplistic and stereotypic ways. Due to the controversy surrounding a chronic fatigue syndrome diagnosis, people with this illness are sometimes overwhelmed with disbelieving attitudes from their doctors, family and/or friends, and many experience profound losses in their support systems (Jason et al., 1997).
One major consequence is that many patients with chronic fatigue syndrome feel dissatisfied with their medical care and some have gone outside traditional medicine to be treated for their illness (Jason, Ferrari, Taylor, Slavich, & Stenzel, 1996). An additional consequence of these negative biases is that few resources have been channeled into developing social and community interventions for this group of individuals. Traditional social service programs often either refuse to treat people with CFS, as they assume that if they look healthy, there must not really be anything physically wrong with them. When treatment is offered, all too frequently the social service personnel will refer the people with CFS to psychiatric services, regardless of whether or not these types of psychiatric services might be needed. Even when social service personnel are sympathetic to the plight of people with this disorder, they rarely have the knowledge or available resources to adequately deal with the needs of people with CFS. Many people with CFS frequently fall through the cracks in the present service delivery system. There is a need to develop model programs that can ultimately be disseminated to those individuals with CFS who need these services.
In addition to experiencing a severe decline in their health and a decrease in their activity levels, many people with CFS experience financial problems as a result of not being able to work (Heiman, 1994). Loss of work can be a devastating and demoralizing experience. Many people with chronic fatigue syndrome believe that there is little hope of finding employment, particularly employment that has a flexible schedule; people with chronic fatigue syndrome may have more energy on some days than on others. Further complicating matters, for those with this syndrome, it is difficult to know one?s energy level from day to day. Flexibility at the work site is a key need for people with chronic fatigue syndrome in search of part-time employment. Furthermore, many people with chronic fatigue syndrome are chemically sensitive and require jobs that are relatively chemical free. For example, a freshly painted office or newly installed carpet might trigger a severe allergic reaction in a person with chronic fatigue syndrome. A recent survey found that as many as 40% of people with multiple chemical sensitivities might have chronic fatigue syndrome (LeRoy, Davis, & Jason, 1996).
Regrettably, there are few job-related programs for people with chronic fatigue syndrome. Most agencies still are not sure how to develop supportive programs for people with severe energy problems. Because people with this syndrome often look ?healthy? when they come into service agencies seeking job counseling or other services, the service providers often do not understand that, at best, people with chronic fatigue syndrome might only have a few hours each week to give to an employer. Full-time employment is not practical for most people with this syndrome.
Because people with chronic fatigue syndrome are often unable to work, many find themselves in danger of losing their housing. Some are forced to move to cheaper dwellings or move back in with their families. We have learned that some people with CFS have been homeless for periods of time. Finding sources of income and affordable housing are two challenges that many people with chronic fatigue syndrome need to cope with while trying to deal with a severely depleted source of energy.
Individuals with CFS are overwhelmingly tired, sometimes finding even brief conversations energy draining. In an effort to conserve energy, particularly during the worst phases, many isolate themselves from friends, family and work. Because of difficulties maintaining employment, many CFS affected individuals have fewer financial resources, and thus they may be forced to seek less than desirable housing. Feeling ill, isolated, and with few resources, it is not surprising that many CFS affected people find themselves confronted with an escalating, downward spiral of negative emotional and physical stressors. For many CFS-affected people, a one-hour monthly self-help group is all that is available.
In order to assess the needs of people with CFS, a recent national survey conducted Jason, Ferrari, Taylor, Slavich, and Stenzel (1997) analyzed the utilization of and preference for a variety of services by people with CFS. It is not surprising that advocacy services were the highest-rated factor, particularly given the discrimination and negative attitudes that people with this disorder have to endure. Preferred advocacy efforts included a telephone hotline service providing immediate advice and assistance on recovery, an advocacy worker to secure financial resources and legitimize the service needs of individuals with CFS, and a volunteer care giver system to provide assistance with daily chores and errands. Respondents with CFS also made a strong plea for needed education within the medical field, government, and general public. Educational efforts would aim to increase knowledge regarding the legitimacy and existence of CFS as a disease entity. In turn, increased knowledge would increase the quality of medical care, financial resources, and services offered for individuals with CFS. Another priority area was self-help groups, which provide emotional support and current treatment information. This result is consistent with other studies indicating that individuals with CFS need continued social and emotional support to cope effectively with their illness. Other areas identified as being of significant need (e.g., housing, jobs, volunteer buddies) were also identified, but no services or programs are currently available in these areas.
Need for a Comprehensive Center:
At the present time, no comprehensive model for patients with CFS exists in the U.S., although there are many excellent programs that do deal with the medical issues facing these people. In addition, once an effective and comprehensive model program is implemented, the information gained from such a program could be used to provide social service personnel appropriate training so that these support service professionals could be more effective in helping people with CFS. The need for such information is clearly indicated in two recent surveys by Heiman (Personal communication, Oct. 20, 1994). He found that 89% of vocational rehabilitation counselors desired more information and/or professional in-service training about CFS, and 94% of physicians, with CFS patients, desired more information about the potential rehabilitation benefits of people with CFS.
Some have argued that a specific agency or service delivery program should not be targeted toward one particular disorder, as it is better to deal with the needs of all people with disabilities. The reality is that there are no agencies that deal comprehensively with the needs of people with CFS. Other groups with disabilities, for example those with spinal cord injuries, have been able to develop new service delivery programs (e.g., Independent Living Centers) when their needs were not being met by existing social service programs. When new illnesses have arisen, for example the case of HIV/AIDS, hundreds of service delivery programs were developed to deal with the needs of people with this disease, and specific federal legislation was written to encourage many of these programs.
Some may wonder whether chronic fatigue syndrome is a potentially reversible disability, for example a medical disorder that will eventually be addressed by pharmacological intervention. If so, than some might argue that the involvement of social service personnel may be phased out as medical progress is made. The prospect for identifying a single etiological agent is uncertain, but even if were to be identified, as with HIV/AIDS, there still would be a need for the development of service programs for those with this illness. Alternatively, if chronic fatigue syndrome does not have a clear cut etiology but is rather a complex disorder involving genetic, constitutional, environmental, and psychological factors, than medication might be palliative but not curative, and the role of the social service personnel will probably be larger and more enduring, involving both advocacy and health promotion.
Some might also argue that the development of service programs might detract from the needed infusion of funds for basic research, and such research is needed in order to find the cause and cure of this disease. There is no reason that two separate agendas can not be pursued, and the appropriations of funds for research and service programs can co-exist and even compliment each other. Most importantly, before critical research breakthroughs occur, there are thousands of individuals who have desperate needs for services to improve the quality of their lives.
A Proposed Multidisciplinary and Mutidimensional CFS Assessment and Treatment Center:
In order to respond to the preferences and needs expressed by people with CFS, a demonstration program needs to be established that provides a place of central access for advocacy, support, and services, as part of an overall CFS assessment and treatment center. A center of this type would organize treatment services and daily living tasks, and act as an advocacy organization to provide needed comprehensive treatment to assist with management of symptoms of this illness. A variety of services could be offered at such a center by medical and social service personnel. A primary-care physician, a nurse, and a psychologist would be available at the center to see patients. Two full time office managers would be available to coordinate the following areas: finance/marketing, legal issues, general assessment policies, triage and referral, housing services, advocacy and program evaluation. One social worker, one rehabilitation counselor, one advocate, and one physical therapist would be hired to develop social service programs. One full-time secretary would be available for record keeping and appointments. Space for a physician’s office, therapist’s office, advocacy worker, rehabilitaiton worker, and physical therapist, and phones for Hotline, and meeting rooms would be provided at the Center.
Advocacy services to counter the discrimination and negative attitudes: An advocacy worker would be hired to help legitimize the service needs of individuals with CFS. Education within the medical field, government, and general public that would aim to increase knowledge regarding the legitimacy and existence of CFS as a disease entity. The advocacy worker will provide education for individuals with CFS and their families and friends, community practitioners, and the general public. Education would focus on increasing understanding of the illness and reducing stigmatization. Physician education would be a high priority activity. The Center staff would maintain regular contacts with and encourage participation in the CFIDS Association of America, Inc., and continuously provide information to the CFIDS Chronicle regarding Center activities.
One of the first steps in dealing with a disability is to be fully informed about the nature of one’s disability, services and benefits which are available and how to access them, laws which protect the rights of persons with disabilities, and community resources for obtaining needed services. The Center would maintain a comprehensive resource and reference library and stay updated on rules and regulations and services of federal, state and local agencies who serve persons with disabilities. This information would be provided to patients, families, friends, professionals, and the general public. The Center would also conduct workshops and seminars, and distribute various flyers and brochures.
Through involvement in committees and advisory boards, meetings with agencies and service providers, and working closely with federal, state, and local officials and representatives, the Center would advocate for the appropriate changes needed to create a community which allows for the acknowledgment and provision of resources for individuals with CFS.
Assessment: Patients would be provided a comprehensive assessment to aid in the selection of an appropriate intervention program. Continuous multidimensional assessment would be an essential element of the program, as the disability experience does not always conform to the methods and requirements of preexisting assessment practices that medical professionals have been trained to apply. The medical assessment would consist of a variety of laboratory tests as well as a complete physical examination, in order to determine what might be the cause of the fatigue. If necessary, specialized tests (e.g., sleep studies) would be ordered to determine possible causes of the symptoms. Neurological and psychological assessments would be administered by a clinical psychologist in order to measure the degree of cognitive, neurological, and psychological impairment resulting from CFS. Furthermore, the assessment would measure general emotional functioning and adjustment to CFS, and determine the appropriateness of individual psychotherapy, couple and/or family counseling, group therapy, psychotropic medications, or a combination of these treatments.
Medical and pharmacological treatment: A physician who specializes in CFS would hold regular office hours to treat various CFS-related physical illnesses and symptoms. The physician would also be available to write needed prescriptions during office hours. A psychiatrist who specializes in treating individuals with CFS would be available for appointments on a weekly basis in order to provide individual eclectic psychotherapy, to write prescriptions for psychotropic medications, and to monitor medication intake. There will be a list of physicians who have particular expertise on topics such as CFS and chronic pain, and the Center physician will make referrals to these specialists if disorders or symptoms are encountered that need these types of services.
Individual, couples, and family psychotherapy: A psychologist and social worker will be available for appointments on a weekly basis to administer various forms of psychotherapy.
Physical therapist: Physicians often tell patients with CFS to be as active as they can, but frequently they provide little specific help on what that might be, and no experience on exactly which exercises will help. The physical therapist will be available to patients to assess activities that might be engaged in and to develop individualized programs of activity.
Case Management: A social worker would be available for full case management of patients with CFS. Sometimes people with CFS need specific help in locating services and filling out paper work for services such as public aid or social security disability. The social worker would be available to insure that the patients had an advocate who would insure that needed and appropriate social services were provided.
Structured self-help educational groups: There will be an ongoing series of six weekly 1 and 1/2 hour self-help educational groups offered at the center for helping individuals who have been newly diagnosed. The sessions will include: etiological, diagnostic and theoretical information about CFS; immune system functioning and enhancement strategies; pain and stress management strategies (including mental imagery, abdominal breathing, meditation, yoga, biofeedback, progressive muscle relaxation, and other relaxation techniques); behavioral coping strategies; information about environmental and structural modification; communication skills and relationship building; and legal, financial, and political issues surrounding disability. If enough children and adolescents with CFS are identified, specific informational groups will be developed for these youngsters and their parents.
Unstructured self-help groups: Unstructured self-help groups would also meet on a weekly basis to provide consumers with a place to express feelings and obtain social and emotional support from those who share a common illness experience.
CFS mentorship program: Individuals who have recovered or significantly adjusted to CFS would be solicited as volunteer mentors for individuals with more severe levels of disability. Some of the mentors would be assigned to program participants in independent living situations and will be available for emotional and informational support regarding CFS.
Volunteer support program: A volunteer care giver system would provide assistance with daily chores and errands. The youthful energy of university students would help persons with chronic fatigue syndrome achieve their independent living goals. Volunteers would help with errands, housekeeping, and cooking if necessary.
Hot-line referral service: A telephone hotline service would be developed to provide immediate advice and assistance on recovery. Hot-line counselors would be provided a referral booklet containing a listing of all possible referral needs including alternative medical specialists, physical therapists, nutritionists, and other mental health workers.
Job assessment, part-time job opportunities, and advocacy to restructure current job responsibilities to maintain one’s employment: First, there will be an assessment of whether the person’s present job can be kept at present health level, considering all benefits available (sick leave and ADA accommodations) and type of profession. Second, if the person with CFS has stabilized and is searching for employment, an assessment will occur (see below). Third, a program will be established to develop job skills and readiness for a job. It should be mentioned that SSA does allow people with disabilities to attempt to return to work, without a reduction in benefitsuntil the person is capable of functioning independently.
A counselor would be responsible to coordinate and to conduct an assessment for determining vocational rehabilitation needs, as appropriate in each individual case. A comprehensive assessment of the unique strengths, resources, priorities, interests, and needs, including the need for supported employment would be performed. A determination of the goals, objectives, nature, and scope of vocational rehabilitation services to be included in the individualized written rehabilitation program of an individual would be conducted. The purpose of this comprehensive assessment would be to obtain information that is necessary to identify the rehabilitation needs of the individual and to develop a personalized rehabilitation program for that individual.
The assessment could include, to the degree needed to make such a determination, an assessment of the personality, interests, interpersonal skills, intelligence and related functional capacities, educational achievements, work experience, vocational aptitudes, personal and social adjustments, and employment opportunities of the individual, and the medical, psychiatric, psychological, and other pertinent vocational, educational, cultural, social, recreational, and environmental factors, that affect the employment and rehabilitation needs of the individual. Dependent on the individual, the assessment could include an appraisal of the patterns of work behavior of the individual and services needed for the individual to acquire occupational skills, and to develop work attitudes, work habits, work tolerance, and social and behavior patterns necessary for successful job performance, including the utilization of work in real job situations to assess and develop the capacities of the individual to perform adequately in a work environment. The complete and thorough assessment would require between 30 days and 90 days, dependent on each individual case in order to allow the counselor to coordinate and obtain necessary information for each client.
The objectives include developing individually written rehabilitation plans by reviewing medical, psychological, social, vocational, aptitudes, abilities, and interests evaluations. Programs will be developed to improve the life style management of participants. Counseling on the impact of CFS on personal relationships, stress and relaxation procedures, coping with problems involving memory and concentration difficulties, job readiness skill attainment, and job placement counseling will be offered to each participant. A counselor would discuss eligibility requirements for obtaining social security benefits, and ways to transition into part-time job opportunities without losing medical and financial benefits of the social security disability program.
A counselor would be available to conduct disability awareness training with the employers of the patients. Specific information about the disability itself and the subsequent impairments and impediments to the work environment would be addressed. The counselor would provide the employer with specific job modification and restructuring plans relative to the individuals needs that can be implemented on the job and help facilitate the individuals return, or entry, to work. Also, rehabilitation legislation training (i.e., The Rehabilitation Act, Section 504, and The Americans with Disability Act) would be given to employers to inform them of the regulations that govern these laws, and their subsequent responsibilities. The counselor would serve as an advocate concerning legal rights, utilization of legal and medical resources available through community rehabilitation programs (i.e., Access Living and other advocacy groups), and financial issues (i.e., health insurance, crisis funding, etc.).
Housing resources: The social worker would establish housing options for people with CFS using section 202. A shared housing program has the potential of providing an inexpensive place to live for those undergoing a crisis situation. The social worker would also develop a shared housing program which will involve others sharing their homes with people with chronic fatigue syndrome.
Other services to be developed:
In order to bring support groups to people who are homebound and/or bedridden, a social worker would provide these individuals computers so that they can participate with on-line support chat rooms. The Center staff would develop and update a directory of resources for people with chronic fatigue syndrome.
A Multidisciplinary and Multidimensional CFS Assessment and Treatment Center is needed now to help persons who are very ill, unable to work, and socially isolated by the debate on specific medical pathology. The proposed Center will bring together appropriate medical professionals to service patients with the best available methods, and provide a place to improve those methods. The Center will also provide a place from which to conduct physician and therapist education on rehabilitating PWCs, a need stated by those professionals in a recent survey.
Approaches to treatment must be comprehensive, addressing a variety of care needs. For example, advocacy focused on securing appropriate medical treatment and on the allocation of government resources for treatment has been cited as a high-priority need for individuals with chronic fatigue syndrome. People with chronic fatigue syndrome desire an advocacy program in which the general public and the medical community becomes better educated about the problems and difficulties associated with chronic fatigue syndrome. Some patients with chronic fatigue syndrome may need assistance from others in order to complete daily living tasks. Living arrangements that include “healthy” individuals to provide for daily, mundane activities may be needed by people with chronic fatigue syndrome, because weakness from this illness might prevent them from accomplishing necessary chores. Finally, a sense of community in which mutual social support is promoted may prevent isolation, depression, and preoccupation with the illness among patients chronic fatigue syndrome.
The dearth of service programs developed to date for patients with CFS might be due to the fact that many physicians continue to believe that chronic fatigue syndrome is predominantly a psychiatric rather than a medical disorder. Frequently physicians treating patients with CFS do not know what to do for their rehabilitation needs, and they are influenced by the idea that it is a psychiatric disease, and as a consequence they often make inappropriate referrals. This Center will be a clear demonstration that there are constructive, therapeutic actions that can be taken beyond diagnosis. Such a Center could ultimately become a training site where open-minded physician can learn to better deal with this disease. We believe that a demonstration program could help the public and medical personnel better understand how comprehensive services can be designed and provided to people with CFS. Besides the immediate help delivered by the proposed Center, it could become a model for Centers elsewhere on the value of a comprehensive approach in the diagnosis and treatment of CFS.
Anderson, J.S., & Ferrans, C.E. (1997). The quality of life of persons with chronic fatigue syndrome. The Journal of Nervous and Mental Disease, 185, 359-367.
Heiman, T. (October 1994). Chronic fatigue syndrome and vocational rehabilitation: Unserved and unmet needs. Paper presented at the American Association of Chronic Fatigue Syndrome Research Conference. Fort Lauderdale, FL.
Jason, L.A., Ferrari, J.R., Taylor, R.R., Slavich, S.P., & Stenzel, C.L. (1996). A national assessment of the service, support, and housing preferences by persons with Chronic Fatigue Syndrome: Toward a comprehensive rehabilitation program. Evaluation and the Health Professions, 19, 194-207.
Jason, L.A., Richman, J.A., Friedberg, F., Wagner, L., Taylor, R., & Jordan, K.M. (1997). Politics, science, and the emergence of a new disease: The case of Chronic Fatigue Syndrome. American Psychologist, 52, 973-983.
Jason, L.A., Wagner, L., Taylor, R., Ropacki, M.T., Shlaes, J., Ferrari, J.R., Slavich, S.P., Stenzel, C. (1995). Chronic Fatigue Syndrome: A new challenge for health care professionals. The Journal of Community Psychology, 23, 143-164.
LeRoy, J., Haney Davis, T., & Jason, L.A. (1996). Treatment efficacy: A survey of 305 MCS patients. The CFIDS Chronicle, 9, 52-53.
Wilson, A., Hickie, I., Lloyd, A., Hadzi-Pavlovic, D., Boughton, C., Dwyer, J., & Wakefield, D. (1994). Longitudinal study of outcome of chronic fatigue syndrome. British Medical Journal, 308, 756-759.